Borane–Trimethylamine Complex: A Versatile Reagent in Organic Synthesis

Borane–trimethylamine complex (Me3N·BH3; BTM) is the most stable of the amine–borane complexes that are commercially available, and it is cost-effective. It is a valuable reagent in organic chemistry with applications in the reduction of carbonyl groups and carbon–nitrogen double bond reduction, with considerable examples in the reduction of oximes, hydrazones and azines. The transfer hydrogenation of aromatic N-heterocycles and the selective N-monomethylation of primary anilines are further examples of recent applications, whereas the reduction of nitrobenzenes to anilines and the reductive deprotection of N-tritylamines are useful tools in the organic synthesis. Moreover, BTM is the main reagent in the regioselective cleavage of cyclic acetals, a reaction of great importance for carbohydrate chemistry. Recent innovative applications of BTM, such as CO2 utilization as feedstock and radical chemistry by photocatalysis, have extended their usefulness in new reactions. The present review is focused on the applications of borane–trimethylamine complex as a reagent in organic synthesis and has not been covered in previous reviews regarding amine–borane complexes.


Introduction
Boron-based reagents play an important role in modern organic synthesis and especially borane carriers have reached a predominant position in the synthesis of pharmaceutics and natural products.Boranes form complexes with Lewis bases, such as amines and pyridines, that are stable, safer and easier to handle.There are few reviews in the literature concerning the use of amine-borane complexes in organic synthesis [1][2][3][4][5][6][7][8], but in some of them, the part describing the reactivity is quite limited.An early review [2] is the most representative in the description of the reactivity of several amine-borane complexes with examples of practical application in organic synthesis covering literature up to 1984; it is also the only one that describes some applications of borane-trimethylamine complex (Me 3 N•BH 3 ; BTM) while the subsequent reviews report either single reactions with this reagent or deal with different amine-boranes.A review on the chemistry of amine and phosphine-boranes was published [3] in 1999, whereas reductive amination was the topic of two reviews, one focused on amine-boranes [5] and the other with several boron reagents [4].Amine-boranes forming frustrated Lewis pairs was the subject of a chapter in a book [6], whereas two recent reviews dealt with the reactivity of ammoniaborane complex [7,8].This review aims to focus on the use of borane-trimethylamine complex as a reagent, mainly after 1984 and not covered in previous reviews regarding amine-borane complexes.
Of the various known complexes, BTM is the most stable [9], less sensitive to hydrolysis, even under acidic conditions [2], and does not require any special storage conditions.It is thermally stable up to 120 • C and can be purified by vacuum sublimation; conversely, ammonia-borane complex explodes when heated, and an attempted distillation of boranepyridine complex at reduced pressure resulted in violent decomposition [1].BTM is very soluble in a wide variety of solvents [1], and its stability significantly increases with increasing solvent polarity [10].It is relatively inexpensive compared with the other amine-borane complexes commercially available and considering the low molecular weight.Contrarily to borane complexes of ammonia, primary and secondary alkylamines, the inert nature of trimethylamine in BTM was a further advantage in avoiding the side reactions observed with the more reactive amines.Its reactivity can be opportunely activated in the reaction medium, and it is considered a valuable reagent in organic synthesis for laboratory as well as industrial scale.Since 1937, when it was synthesized for the first time, its applications have grown steadily, with some innovative ones in recent years.

Reduction of Ketones
BTM is a weak hydride donor more reactive than trialkylsilanes and trialkylgermanes, comparable with that of trialkylstannanes [11].The greater stability of BTM in the presence of Lewis or Brønsted acid allows the activation of the substrate by acid catalysis [2]; from kinetic studies, the rate of reduction of aldehydes and ketones increases with increasing acidity of the medium suggesting the formation of a protonated carbonyl species in rapid equilibrium, followed by the rate-determining step of the reduction.BTM was the reagent of choice for the selective reduction of steroidal diones, such as 1, in the presence of wet silica gel impregnated with FeCl 3 (Scheme 1): C-3 carbonyl group was reduced preferentially to the alcohol 2 [12].
decomposition [1].BTM is very soluble in a wide variety of solvents [1], and its stab significantly increases with increasing solvent polarity [10].It is relatively inexpen compared with the other amine-borane complexes commercially available considering the low molecular weight.Contrarily to borane complexes of ammo primary and secondary alkylamines, the inert nature of trimethylamine in BTM w further advantage in avoiding the side reactions observed with the more reactive ami Its reactivity can be opportunely activated in the reaction medium, and it is consider valuable reagent in organic synthesis for laboratory as well as industrial scale.Since 1 when it was synthesized for the first time, its applications have grown steadily, with s innovative ones in recent years.

Reduction of Ketones
BTM is a weak hydride donor more reactive than trialkylsilanes trialkylgermanes, comparable with that of trialkylstannanes [11].The greater stabilit BTM in the presence of Lewis or Brønsted acid allows the activation of the substrat acid catalysis [2]; from kinetic studies, the rate of reduction of aldehydes and keto increases with increasing acidity of the medium suggesting the formation of a proton carbonyl species in rapid equilibrium, followed by the rate-determining step of reduction.BTM was the reagent of choice for the selective reduction of steroidal dio such as 1, in the presence of wet silica gel impregnated with FeCl3 (Scheme 1): C-3 carb group was reduced preferentially to the alcohol 2 [12].Scheme 1. Regioselective reduction of dione 1 on a silica gel surface.
The formation of a chelate between the Lewis acid and substrates 3 and 5 prove be effective for the completely diastereoselective reduction to the corresponding alco 4 and 6 (Scheme 2) [13].In a similar way, in the enantioselective total synthesis of analogs of griseusins ketone 7 was reduced by BTM in good diastereoselectivity using TFA as acid (Schem Scheme 1. Regioselective reduction of dione 1 on a silica gel surface. The formation of a chelate between the Lewis acid and substrates 3 and 5 proved to be effective for the completely diastereoselective reduction to the corresponding alcohols 4 and 6 (Scheme 2) [13].
significantly increases with increasing solvent polarity [10].It is relatively inexpen compared with the other amine-borane complexes commercially available considering the low molecular weight.Contrarily to borane complexes of ammo primary and secondary alkylamines, the inert nature of trimethylamine in BTM w further advantage in avoiding the side reactions observed with the more reactive am Its reactivity can be opportunely activated in the reaction medium, and it is consider valuable reagent in organic synthesis for laboratory as well as industrial scale.Since 1 when it was synthesized for the first time, its applications have grown steadily, with s innovative ones in recent years.

Reduction of Ketones
BTM is a weak hydride donor more reactive than trialkylsilanes trialkylgermanes, comparable with that of trialkylstannanes [11].The greater stabilit BTM in the presence of Lewis or Brønsted acid allows the activation of the substrat acid catalysis [2]; from kinetic studies, the rate of reduction of aldehydes and ket increases with increasing acidity of the medium suggesting the formation of a proton carbonyl species in rapid equilibrium, followed by the rate-determining step of reduction.BTM was the reagent of choice for the selective reduction of steroidal dio such as 1, in the presence of wet silica gel impregnated with FeCl3 (Scheme 1): C-3 carb group was reduced preferentially to the alcohol 2 [12].The formation of a chelate between the Lewis acid and substrates 3 and 5 prove be effective for the completely diastereoselective reduction to the corresponding alco 4 and 6 (Scheme 2) [13].In a similar way, in the enantioselective total synthesis of analogs of griseusins ketone 7 was reduced by BTM in good diastereoselectivity using TFA as acid (Schem In a similar way, in the enantioselective total synthesis of analogs of griseusins [14], ketone 7 was reduced by BTM in good diastereoselectivity using TFA as acid (Scheme 3).

Reductive Bromation of Aromatic Carbonyl Compounds
Bromine was an effective activator in the reduction of both aldehydes and ketones by BTM [15], but in the case of aromatic compounds 9, the reaction proceeded beyond th reduction to alcohol, leading to bromide derivative 10 in good yields (Scheme 4) with th exception of a product obtained in low yield after recrystallization.Some useful exploitations of the synthetic method were (Scheme 5) the synthesis o the 14 C labeled benzylbromide 12, intermediate in the synthesis of CX3CR1 antagonist 1 [16], and the synthesis of the dibromide derivative 15, intermediate in the synthesis o crownophanes [17].
Scheme 5. Synthesis of the 14 C labeled benzylbromide 12 and the dibromide derivative 15.

Reduction of Carboxylic Acids
At room temperature, carboxylic acids are inert in presence of BTM and can be used as solvent in the reduction reactions; on the other hand, refluxing a xylene solution of BTM and carboxylic acid 16 in molar ratio of 1.5:2, ester 17 was isolated in 87% yield [18 (Scheme 6); the reaction was suitable both to aliphatic and aromatic acids with moderat to good yields (28-87%).

Reductive Bromation of Aromatic Carbonyl Compounds
Bromine was an effective activator in the reduction of both aldehydes and ketones by BTM [15], but in the case of aromatic compounds 9, the reaction proceeded beyond the reduction to alcohol, leading to bromide derivative 10 in good yields (Scheme 4) with the exception of a product obtained in low yield after recrystallization.

Reductive Bromation of Aromatic Carbonyl Compounds
Bromine was an effective activator in the reduction of both aldehydes and ketones by BTM [15], but in the case of aromatic compounds 9, the reaction proceeded beyond th reduction to alcohol, leading to bromide derivative 10 in good yields (Scheme 4) with th exception of a product obtained in low yield after recrystallization.Some useful exploitations of the synthetic method were (Scheme 5) the synthesis o the 14 C labeled benzylbromide 12, intermediate in the synthesis of CX3CR1 antagonist 1 [16], and the synthesis of the dibromide derivative 15, intermediate in the synthesis o crownophanes [17].

Reduction of Carboxylic Acids
At room temperature, carboxylic acids are inert in presence of BTM and can be used as solvent in the reduction reactions; on the other hand, refluxing a xylene solution of BTM and carboxylic acid 16 in molar ratio of 1.5:2, ester 17 was isolated in 87% yield [18 (Scheme 6); the reaction was suitable both to aliphatic and aromatic acids with moderat to good yields (28-87%).Some useful exploitations of the synthetic method were (Scheme 5) the synthesis of the 14 C labeled benzylbromide 12, intermediate in the synthesis of CX 3 CR1 antagonist 13 [16], and the synthesis of the dibromide derivative 15, intermediate in the synthesis of crownophanes [17].

Reductive Bromation of Aromatic Carbonyl Compounds
Bromine was an effective activator in the reduction of both aldehydes and ketones by BTM [15], but in the case of aromatic compounds 9, the reaction proceeded beyond the reduction to alcohol, leading to bromide derivative 10 in good yields (Scheme 4) with the exception of a product obtained in low yield after recrystallization.Some useful exploitations of the synthetic method were (Scheme 5) the synthesis of the 14 C labeled benzylbromide 12, intermediate in the synthesis of CX3CR1 antagonist 13 [16], and the synthesis of the dibromide derivative 15, intermediate in the synthesis of crownophanes [17].

Reduction of Carboxylic Acids
At room temperature, carboxylic acids are inert in presence of BTM and can be used as solvent in the reduction reactions; on the other hand, refluxing a xylene solution of BTM and carboxylic acid 16 in molar ratio of 1.5:2, ester 17 was isolated in 87% yield [18] (Scheme 6); the reaction was suitable both to aliphatic and aromatic acids with moderate to good yields (28-87%).

Reduction of Carboxylic Acids
At room temperature, carboxylic acids are inert in presence of BTM and can be used as solvent in the reduction reactions; on the other hand, refluxing a xylene solution of BTM and carboxylic acid 16 in molar ratio of 1.5:2, ester 17 was isolated in 87% yield [18] (Scheme 6); the reaction was suitable both to aliphatic and aromatic acids with moderate to good yields (28-87%).A plausible reaction mechanism could be the presence of two concurrent reactions the reduction of the acid 18 to alcohol 19, isolated in every reaction, and the formation of the triacyloxyborane complex 20, a known acylating compound; finally, the reaction of the two intermediates leads to the ester 21 (Scheme 7).By adding either primary or secondary amine 22 to the previous reaction mixture and changing the ratio of the reagents, a different result was obtained (Scheme 8) [19] with the molar ratio BTM:amine 22:acid 18 = 1:1:3 led to amide 23, seemingly by the action of acylating complex 20; instead, the molar ratio 1:2:2 led to the tertiary amine 24, likely by reduction of the acid 18 to an aldehyde equivalent (boryl acetal) followed by the reductive alkylation of amine 22.

Reductive Methylation with CO2
Recently, the reduction of CO2 has emerged as a topic of great interest connected with global climate change and the urgent necessity to reduce the concentration of CO2 in the atmosphere through sequestration and its utilization in the synthesis of usefu compounds.An early study [20] reported the reduction of CO2 to formate by BTM weakly bonded to the bulkier Lewis acid Al(C6F5)3; then, the reaction mechanism was studied by quantum chemical calculations [21].Subsequently, the reduction of CO2 was exploited for the selective monomethylation of 2-arylacetonitriles 25 [22]; as shown in Scheme 9, the optimized reaction conditions involved the reaction, in a sealed tube, of a DME solution of nitrile 25, t BuOK and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in an atmosphere of CO2 obtaining selectively the monomethyl derivative 26, with yields around 80% in almost al examples.A plausible reaction mechanism could be the presence of two concurrent reactions: the reduction of the acid 18 to alcohol 19, isolated in every reaction, and the formation of the triacyloxyborane complex 20, a known acylating compound; finally, the reaction of the two intermediates leads to the ester 21 (Scheme 7).A plausible reaction mechanism could be the presence of two concurrent reactions the reduction of the acid 18 to alcohol 19, isolated in every reaction, and the formation of the triacyloxyborane complex 20, a known acylating compound; finally, the reaction of the two intermediates leads to the ester 21 (Scheme 7).By adding either primary or secondary amine 22 to the previous reaction mixture and changing the ratio of the reagents, a different result was obtained (Scheme 8) [19] with the molar ratio BTM:amine 22:acid 18 = 1:1:3 led to amide 23, seemingly by the action of acylating complex 20; instead, the molar ratio 1:2:2 led to the tertiary amine 24, likely by reduction of the acid 18 to an aldehyde equivalent (boryl acetal) followed by the reductive alkylation of amine 22.

Reductive Methylation with CO2
Recently, the reduction of CO2 has emerged as a topic of great interest connected with global climate change and the urgent necessity to reduce the concentration of CO2 in the atmosphere through sequestration and its utilization in the synthesis of usefu compounds.An early study [20] reported the reduction of CO2 to formate by BTM weakly bonded to the bulkier Lewis acid Al(C6F5)3; then, the reaction mechanism was studied by quantum chemical calculations [21].Subsequently, the reduction of CO2 was exploited for the selective monomethylation of 2-arylacetonitriles 25 [22]; as shown in Scheme 9, the optimized reaction conditions involved the reaction, in a sealed tube, of a DME solution of nitrile 25, t BuOK and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in an atmosphere of CO2 obtaining selectively the monomethyl derivative 26, with yields around 80% in almost al examples.By adding either primary or secondary amine 22 to the previous reaction mixture and changing the ratio of the reagents, a different result was obtained (Scheme 8) [19]: with the molar ratio BTM:amine 22:acid 18 = 1:1:3 led to amide 23, seemingly by the action of acylating complex 20; instead, the molar ratio 1:2:2 led to the tertiary amine 24, likely by reduction of the acid 18 to an aldehyde equivalent (boryl acetal) followed by the reductive alkylation of amine 22.A plausible reaction mechanism could be the presence of two concurrent reactions the reduction of the acid 18 to alcohol 19, isolated in every reaction, and the formation of the triacyloxyborane complex 20, a known acylating compound; finally, the reaction of the two intermediates leads to the ester 21 (Scheme 7).By adding either primary or secondary amine 22 to the previous reaction mixture and changing the ratio of the reagents, a different result was obtained (Scheme 8) [19] with the molar ratio BTM:amine 22:acid 18 = 1:1:3 led to amide 23, seemingly by the action of acylating complex 20; instead, the molar ratio 1:2:2 led to the tertiary amine 24, likely by reduction of the acid 18 to an aldehyde equivalent (boryl acetal) followed by the reductive alkylation of amine 22.

Reductive Methylation with CO2
Recently, the reduction of CO2 has emerged as a topic of great interest connected with global climate change and the urgent necessity to reduce the concentration of CO2 in the atmosphere through sequestration and its utilization in the synthesis of useful compounds.An early study [20] reported the reduction of CO2 to formate by BTM weakly bonded to the bulkier Lewis acid Al(C6F5)3; then, the reaction mechanism was studied by quantum chemical calculations [21].Subsequently, the reduction of CO2 was exploited for the selective monomethylation of 2-arylacetonitriles 25 [22]; as shown in Scheme 9, the optimized reaction conditions involved the reaction, in a sealed tube, of a DME solution of nitrile 25, t BuOK and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in an atmosphere of CO2 obtaining selectively the monomethyl derivative 26, with yields around 80% in almost all examples.

Reductive Methylation with CO 2
Recently, the reduction of CO 2 has emerged as a topic of great interest connected with global climate change and the urgent necessity to reduce the concentration of CO 2 in the atmosphere through sequestration and its utilization in the synthesis of useful compounds.An early study [20] reported the reduction of CO 2 to formate by BTM weakly bonded to the bulkier Lewis acid Al(C 6 F 5 ) 3 ; then, the reaction mechanism was studied by quantum chemical calculations [21].Subsequently, the reduction of CO 2 was exploited for the selective monomethylation of 2-arylacetonitriles 25 [22]; as shown in Scheme 9, the optimized reaction conditions involved the reaction, in a sealed tube, of a DME solution of nitrile 25, t BuOK and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in an atmosphere of CO 2 , obtaining selectively the monomethyl derivative 26, with yields around 80% in almost all examples.By using 13 CO2, the corresponding 13 C methyl derivative was obtained, confirming that the methyl group comes from CO2.In the reaction, TBD has the role of activator o the CO2 forming the adduct 27 (Scheme 10), and t BuOK of a strong base in deprotonation of 2-arylacetonitriles 25.The reaction, shown in Scheme 9, performed without nitrile 25 led to methyl borate 29 as the major product, which suggests that CO2 undergoes a six electron reduction with the formatoborohydride 28 as an intermediate.Differently from BTM, borane-ammonia complex reduced CO2 to the formyl group; conversely, with the borane dimethylamine complex (BDM), the two-electron reduction product 28 reacted with dimethylamine, derived from BDM, leading to amide 30 and blocking further reduction (Scheme 10).In the presence of t BuOK, methyl borate 29 proved to be an effective methylating agent of nitrile 25, obtaining the methylated product 26 in 75% yield in a similar way, two different nucleophiles, such as aniline 31 and thiophenol 33, were methylated in the same reaction condition.By using 13 CO 2, the corresponding 13 C methyl derivative was obtained, confirming that the methyl group comes from CO 2 .In the reaction, TBD has the role of activator of the CO 2 forming the adduct 27 (Scheme 10), and t BuOK of a strong base in deprotonation of 2-arylacetonitriles 25.The reaction, shown in Scheme 9, performed without nitrile 25, led to methyl borate 29 as the major product, which suggests that CO 2 undergoes a sixelectron reduction with the formatoborohydride 28 as an intermediate.Differently from BTM, borane-ammonia complex reduced CO 2 to the formyl group; conversely, with the borane dimethylamine complex (BDM), the two-electron reduction product 28 reacted with dimethylamine, derived from BDM, leading to amide 30 and blocking further reduction (Scheme 10).In the presence of t BuOK, methyl borate 29 proved to be an effective methylating agent of nitrile 25, obtaining the methylated product 26 in 75% yield; in a similar way, two different nucleophiles, such as aniline 31 and thiophenol 33, were methylated in the same reaction condition.By using 13 CO2, the corresponding 13 C methyl derivative was obtained, confirming that the methyl group comes from CO2.In the reaction, TBD has the role of activator of the CO2 forming the adduct 27 (Scheme 10), and t BuOK of a strong base in deprotonation of 2-arylacetonitriles 25.The reaction, shown in Scheme 9, performed without nitrile 25, led to methyl borate 29 as the major product, which suggests that CO2 undergoes a sixelectron reduction with the formatoborohydride 28 as an intermediate.Differently from BTM, borane-ammonia complex reduced CO2 to the formyl group; conversely, with the borane dimethylamine complex (BDM), the two-electron reduction product 28 reacted with dimethylamine, derived from BDM, leading to amide 30 and blocking further reduction (Scheme 10).In the presence of t BuOK, methyl borate 29 proved to be an effective methylating agent of nitrile 25, obtaining the methylated product 26 in 75% yield; in a similar way, two different nucleophiles, such as aniline 31 and thiophenol 33, were methylated in the same reaction condition.By using 13 CO2, the corresponding 13 C methyl derivative was obtained, confirming that the methyl group comes from CO2.In the reaction, TBD has the role of activator o the CO2 forming the adduct 27 (Scheme 10), and t BuOK of a strong base in deprotonation of 2-arylacetonitriles 25.The reaction, shown in Scheme 9, performed without nitrile 25 led to methyl borate 29 as the major product, which suggests that CO2 undergoes a six electron reduction with the formatoborohydride 28 as an intermediate.Differently from BTM, borane-ammonia complex reduced CO2 to the formyl group; conversely, with the borane dimethylamine complex (BDM), the two-electron reduction product 28 reacted with dimethylamine, derived from BDM, leading to amide 30 and blocking further reduction (Scheme 10).In the presence of t BuOK, methyl borate 29 proved to be an effective methylating agent of nitrile 25, obtaining the methylated product 26 in 75% yield in a similar way, two different nucleophiles, such as aniline 31 and thiophenol 33, were methylated in the same reaction condition.On the basis of a series of control experiments, NMR and high-resolution mass spectrometry (HRMS) analyses, a possible reaction mechanism was proposed (Scheme 12).The first step is the reaction of 6-amino-2-picoline 36 and excess BTM leading to aminoborane 38, with the quantitative evolution of H2, followed by the CO2 activation with zwitterionic intermediate 39.The next steps are less evident, and the authors speculate the formation of intermediate 40 that is further reduced to product 37. Scheme 12. Reaction mechanism of methylation of amines with CO2.
Without a catalyst, halving the equivalents of BTM and with DMF as solvent (Scheme 13), the reduction afforded the corresponding monoformylation products 41, an intermediate hypothesized in the reduction from 40 to product 37 (Scheme 12); most of the amines 35 used were primary anilines and yields were generally good.Finally, a tandem four-component reductive methylation of primary amines 42 was realized, coupling a reductive amination to secondary amines 45, with the reduction of CO2 to a methyl group, synthesizing tertiary N-methylamines 46 [24] (Scheme 14).Scheme 14. Four-component reductive methylation of primary amines with CO2.
On the contrary of catalyst 36, 2-aminothiazole 44 catalyzed the reaction with higher efficiency, whereas BTM was the best choice in the screening of different types of boronbased reducing agents.The study of the scope of the reaction involved a large number of amines 42, aldehydes and ketones 43, leading to products in mostly good yields; the gramscale synthesis of the antifungal agent butenafine 49 was an example of the potentiality of the present synthetic method (Scheme 15).Finally, a tandem four-component reductive methylation of primary amines 42 was realized, coupling a reductive amination to secondary amines 45, with the reduction of CO2 to a methyl group, synthesizing tertiary N-methylamines 46 [24] (Scheme 14).Scheme 14. Four-component reductive methylation of primary amines with CO2.
On the contrary of catalyst 36, 2-aminothiazole 44 catalyzed the reaction with higher efficiency, whereas BTM was the best choice in the screening of different types of boronbased reducing agents.The study of the scope of the reaction involved a large number of amines 42, aldehydes and ketones 43, leading to products in mostly good yields; the gramscale synthesis of the antifungal agent butenafine 49 was an example of the potentiality of the present synthetic method (Scheme 15).Finally, a tandem four-component reductive methylation of primary amines 42 was realized, coupling a reductive amination to secondary amines 45, with the reduction of CO 2 to a methyl group, synthesizing tertiary N-methylamines 46 [24] (Scheme 14).Finally, a tandem four-component reductive methylation of primary amines 42 was realized, coupling a reductive amination to secondary amines 45, with the reduction of CO2 to a methyl group, synthesizing tertiary N-methylamines 46 [24] (Scheme 14).Scheme 14. Four-component reductive methylation of primary amines with CO2.
On the contrary of catalyst 36, 2-aminothiazole 44 catalyzed the reaction with higher efficiency, whereas BTM was the best choice in the screening of different types of boronbased reducing agents.The study of the scope of the reaction involved a large number of amines 42, aldehydes and ketones 43, leading to products in mostly good yields; the gramscale synthesis of the antifungal agent butenafine 49 was an example of the potentiality of the present synthetic method (Scheme 15).On the contrary of catalyst 36, 2-aminothiazole 44 catalyzed the reaction with higher efficiency, whereas BTM was the best choice in the screening of different types of boronbased reducing agents.The study of the scope of the reaction involved a large number of amines 42, aldehydes and ketones 43, leading to products in mostly good yields; the gramscale synthesis of the antifungal agent butenafine 49 was an example of the potentiality of the present synthetic method (Scheme 15).Scheme 15.Synthesis of the antifungal agent butenafine 49.

Reduction of Hydrazones and Azines
Although the reduction of hydrazones and azines is hampered by opposite conjugation effects, the presence of an acid in the reaction medium can activate the C=N bond to the attack of nucleophiles [25,26].The improved stability of BTM in a strong acidic medium enabled the efficient reduction of both hydrazones 50 and azines 52 (Scheme 16), affording a wide range of highly functionalized mono-, di-and trialkyl hydrazines as stable and safe hydrochlorides and in excellent yields for most of the compounds.The work-up operationally simple was another credit of the method, as the byproduct of reduction 56 (Scheme 17) was soluble in toluene, contrary to products 51 or 53, which are completely insoluble (except for two compounds) and easily separated by filtration.Byproduct 56 was exploited in the "one pot" synthesis of hydrazides by adding carboxylic acid 57 at the end of the reduction step and producing, in situ, a mixture of Scheme 15.Synthesis of the antifungal agent butenafine 49.

Reduction of Hydrazones and Azines
Although the reduction of hydrazones and azines is hampered by opposite conjugation effects, the presence of an acid in the reaction medium can activate the C=N bond to the attack of nucleophiles [25,26].The improved stability of BTM in a strong acidic medium enabled the efficient reduction of both hydrazones 50 and azines 52 (Scheme 16), affording a wide range of highly functionalized mono-, di-and trialkyl hydrazines as stable and safe hydrochlorides and in excellent yields for most of the compounds.

Reduction of Hydrazones and Azines
Although the reduction of hydrazones and azines is hampered by opposite conjugation effects, the presence of an acid in the reaction medium can activate the C=N bond to the attack of nucleophiles [25,26].The improved stability of BTM in a strong acidic medium enabled the efficient reduction of both hydrazones 50 and azines 52 (Scheme 16), affording a wide range of highly functionalized mono-, di-and trialkyl hydrazines as stable and safe hydrochlorides and in excellent yields for most of the compounds.The work-up operationally simple was another credit of the method, as the byproduct of reduction 56 (Scheme 17) was soluble in toluene, contrary to products 51 or 53, which are completely insoluble (except for two compounds) and easily separated by filtration.Byproduct 56 was exploited in the "one pot" synthesis of hydrazides by adding carboxylic acid 57 at the end of the reduction step and producing, in situ, a mixture of

Reduction of Hydrazones and Azines
Although the reduction of hydrazones and azines is hampered by opposite conjugation effects, the presence of an acid in the reaction medium can activate the C=N bond to the attack of nucleophiles [25,26].The improved stability of BTM in a strong acidic medium enabled the efficient reduction of both hydrazones 50 and azines 52 (Scheme 16), affording a wide range of highly functionalized mono-, di-and trialkyl hydrazines as stable and safe hydrochlorides and in excellent yields for most of the compounds.The work-up operationally simple was another credit of the method, as the byproduct of reduction 56 (Scheme 17) was soluble in toluene, contrary to products 51 or 53, which are completely insoluble (except for two compounds) and easily separated by filtration.Byproduct 56 was exploited in the "one pot" synthesis of hydrazides by adding carboxylic acid 57 at the end of the reduction step and producing, in situ, a mixture of Scheme 17.The proposed mechanism of the synthesis of hydrazides.
Byproduct 56 was exploited in the "one pot" synthesis of hydrazides by adding carboxylic acid 57 at the end of the reduction step and producing, in situ, a mixture of acyloxyboranes 58 (Scheme 17) that proved to be an effective acylating agent of both alkylhydrazine hydrochloride 51 and 53 (Scheme 18); the yields were susceptible to the bulkiness of both carboxylic acids and alkylhydrazines limiting the reaction to less hindered hydrazones and azines derived from aldehydes.The tight steric requirement for the acylation by the acyloxyboranes made the synthesis of hydrazides 60 completely selective without the formation of the related diacyl hydrazines side-product, generally observed with common acylating agents.
Molecules 2024, 29, 2017 8 of 23 acyloxyboranes 58 (Scheme 17) that proved to be an effective acylating agent of both alkylhydrazine hydrochloride 51 and 53 (Scheme 18); the yields were susceptible to the bulkiness of both carboxylic acids and alkylhydrazines limiting the reaction to less hindered hydrazones and azines derived from aldehydes.The tight steric requirement for the acylation by the acyloxyboranes made the synthesis of hydrazides 60 completely selective without the formation of the related diacyl hydrazines side-product, generally observed with common acylating agents.

Reduction of Oximes
Early studies on the reduction of oximes by BTM and HCl were directed to the synthesis of N-hydroxy derivatives of tryptophan 62 (Scheme 19), useful intermediates for the synthesis of β-Carbolines [27-30], fungal metabolites Neoechinulins [31,32] and recently the marine fungal metabolite raistrickindole A [33] (Scheme 20); with some oximes the reduction of indole to indoline (see Section 3.3) was observed [32].Subsequently, the synthetic method was extended to the synthesis of a new type of pseudopeptides, the N-hydroxy dipeptides 66 [34], as a diastereoisomeric mixture (Scheme 21).

Reduction of Oximes
Early studies on the reduction of oximes by BTM and HCl were directed to the synthesis of N-hydroxy derivatives of tryptophan 62 (Scheme 19), useful intermediates for the synthesis of β-Carbolines [27-30], fungal metabolites Neoechinulins [31,32] and recently the marine fungal metabolite raistrickindole A [33] (Scheme 20); with some oximes the reduction of indole to indoline (see Section 3.3) was observed [32].
Molecules 2024, 29, 2017 8 of 23 acyloxyboranes 58 (Scheme 17) that proved to be an effective acylating agent of both alkylhydrazine hydrochloride 51 and 53 (Scheme 18); the yields were susceptible to the bulkiness of both carboxylic acids and alkylhydrazines limiting the reaction to less hindered hydrazones and azines derived from aldehydes.The tight steric requirement for the acylation by the acyloxyboranes made the synthesis of hydrazides 60 completely selective without the formation of the related diacyl hydrazines side-product, generally observed with common acylating agents.

Reduction of Oximes
Early studies on the reduction of oximes by BTM and HCl were directed to the synthesis of N-hydroxy derivatives of tryptophan 62 (Scheme 19), useful intermediates for the synthesis of β-Carbolines [27-30], fungal metabolites Neoechinulins [31,32] and recently the marine fungal metabolite raistrickindole A [33] (Scheme 20); with some oximes the reduction of indole to indoline (see Section 3.3) was observed [32].Subsequently, the synthetic method was extended to the synthesis of a new type of pseudopeptides, the N-hydroxy dipeptides 66 [34], as a diastereoisomeric mixture (Scheme 21).acyloxyboranes 58 (Scheme 17) that proved to be an effective acylating agent of both alkylhydrazine hydrochloride 51 and 53 (Scheme 18); the yields were susceptible to the bulkiness of both carboxylic acids and alkylhydrazines limiting the reaction to less hindered hydrazones and azines derived from aldehydes.The tight steric requirement for the acylation by the acyloxyboranes made the synthesis of hydrazides 60 completely selective without the formation of the related diacyl hydrazines side-product, generally observed with common acylating agents.

Reduction of Oximes
Early studies on the reduction of oximes by BTM and HCl were directed to the synthesis of N-hydroxy derivatives of tryptophan 62 (Scheme 19), useful intermediates for the synthesis of β-Carbolines [27-30], fungal metabolites Neoechinulins [31,32] and recently the marine fungal metabolite raistrickindole A [33] (Scheme 20); with some oximes the reduction of indole to indoline (see Section 3.3) was observed [32].Subsequently, the synthetic method was extended to the synthesis of a new type of pseudopeptides, the N-hydroxy dipeptides 66 [34], as a diastereoisomeric mixture (Scheme 21).Subsequently, the synthetic method was extended to the synthesis of a new type of pseudopeptides, the N-hydroxy dipeptides 66 [34], as a diastereoisomeric mixture (Scheme 21).Scheme 21.Synthesis of N-hydroxy dipeptides.
Reduction of oximes was the easiest method of synthesis of the N-alkylhydroxylamines 68 [35], requisite for the neoglycosylation reaction optimization in the synthesis of glycosylated 69 (Scheme 22); the yields were mediocre to moderate, likely due to the use of diluted HCl aqueous solution.Similarly, the betulinic derivative 71 [36] and 9-amino doxycycline derivative 73 [37] suitable substrates for the neoglycosylation reaction, were synthesized from the corresponding oximes in good yields, making use of HCl in ethanol and large excess of BTM (Scheme 23).Finally, a new fluorous-tagged hydroxylamine [38], as an ammonia equivalent, was successfully exploited in the synthesis of itopride, a drug used for the treatment of functional dyspepsia; the work-up step was simplified by fluorous solid-phase extraction (F-SPE), relative with this strategy (Scheme 24).Reduction of oximes was the easiest method of synthesis of the N-alkyl-hydroxylamines 68 [35], requisite for the neoglycosylation reaction optimization in the synthesis of glycosylated 69 (Scheme 22); the yields were mediocre to moderate, likely due to the use of diluted HCl aqueous solution.Reduction of oximes was the easiest method of synthesis of the N-alkyl hydroxylamines 68 [35], requisite for the neoglycosylation reaction optimization in the synthesis of glycosylated 69 (Scheme 22); the yields were mediocre to moderate, likely due to the use of diluted HCl aqueous solution.Similarly, the betulinic derivative 71 [36] and 9-amino doxycycline derivative 73 [37] suitable substrates for the neoglycosylation reaction, were synthesized from the corresponding oximes in good yields, making use of HCl in ethanol and large excess o BTM (Scheme 23).Finally, a new fluorous-tagged hydroxylamine [38], as an ammonia equivalent, was successfully exploited in the synthesis of itopride, a drug used for the treatment o functional dyspepsia; the work-up step was simplified by fluorous solid-phase extraction (F-SPE), relative with this strategy (Scheme 24).Similarly, the betulinic derivative 71 [36] and 9-amino doxycycline derivative 73 [37], suitable substrates for the neoglycosylation reaction, were synthesized from the corresponding oximes in good yields, making use of HCl in ethanol and large excess of BTM (Scheme 23).Reduction of oximes was the easiest method of synthesis of the N-alkylhydroxylamines 68 [35], requisite for the neoglycosylation reaction optimization in the synthesis of glycosylated 69 (Scheme 22); the yields were mediocre to moderate, likely due to the use of diluted HCl aqueous solution.Similarly, the betulinic derivative 71 [36] and 9-amino doxycycline derivative 73 [37], suitable substrates for the neoglycosylation reaction, were synthesized from the corresponding oximes in good yields, making use of HCl in ethanol and large excess of BTM (Scheme 23).Finally, a new fluorous-tagged hydroxylamine [38], as an ammonia equivalent, was successfully exploited in the synthesis of itopride, a drug used for the treatment of functional dyspepsia; the work-up step was simplified by fluorous solid-phase extraction (F-SPE), relative with this strategy (Scheme 24).Finally, a new fluorous-tagged hydroxylamine [38], as an ammonia equivalent, was successfully exploited in the synthesis of itopride, a drug used for the treatment of functional dyspepsia; the work-up step was simplified by fluorous solid-phase extraction (F-SPE), relative with this strategy (Scheme 24).

Transfer Hydrogenation of Aromatic N-Heterocycles
Several aromatic N-heterocycles can react with protic acid or acylating agents leading to salts with an immonium substructure that can be reduced by BTM similarly to the reduction of imines activated with protic acid [2]; reduction of indoles to indoline was reported in a previous review [2].

Transfer Hydrogenation of Aromatic N-Heterocycles
Several aromatic N-heterocycles can react with protic acid or acylating agents, leading to salts with an immonium substructure that can be reduced by BTM similarly to the reduction of imines activated with protic acid [2]; reduction of indoles to indolines was reported in a previous review [2].
BTM reduced pyridines 76 (Scheme 25), activated by reaction with phenyl chloroformate, to 1,4 dihydropyridine 77 (majority product) and 1,2 dihydropyridine 78 (minority product) [39]; the use of triflic anhydride improved the regioselectivity toward dihydropyridine 77 reaching, in the best case, the 99:1 regioselectivity and 76:24 for the worst case.Substituents in the 4-position completely inverted the selectivity in favor of regioisomer 78.The reaction could also be applied for the synthesis of other N-heterocycles, such as dihydroquinolines 79, dihydroisoquinolines 80 and benzothiazoline 81, among others.

Transfer Hydrogenation of Aromatic N-Heterocycles
Several aromatic N-heterocycles can react with protic acid or acylating agents leading to salts with an immonium substructure that can be reduced by BTM similarly to the reduction of imines activated with protic acid [2]; reduction of indoles to indolines was reported in a previous review [2].
BTM reduced pyridines 76 (Scheme 25), activated by reaction with pheny chloroformate, to 1,4 dihydropyridine 77 (majority product) and 1,2 dihydropyridine 78 (minority product) [39]; the use of triflic anhydride improved the regioselectivity toward dihydropyridine 77 reaching, in the best case, the 99:1 regioselectivity and 76:24 for the worst case.Substituents in the 4-position completely inverted the selectivity in favor of regioisomer 78.The reaction could also be applied for the synthesis of other Nheterocycles, such as dihydroquinolines 79, dihydroisoquinolines 80 and benzothiazoline 81, among others.Trifluoroacetic acid (TFA), as an acidic activator, offered several opportunities; both indoles 82 and quinoxalines 84 [40] were reduced to indolines 83 and tetrahydroquinoxalines 85, respectively, in water as solvent (Scheme 26).Trifluoroacetic acid (TFA), as an acidic activator, offered several opportunities; both indoles 82 and quinoxalines 84 [40] were reduced to indolines 83 and tetrahydroquinoxalines 85, respectively, in water as solvent (Scheme 26).Tuning the reaction condition and the equivalents of BTM and TFA, as shown in Scheme 27, to go beyond the reduction, obtaining a different product [41].A reduced amount of BTM, increased equivalents of TFA and the use of an aprotic solvent brought to the N-trifluoroacetylated indolines 86, while the increase of BTM brought to the Ntrifluoroethylated indolines 87, similarly to the reduction, by BTM, of carboxylic acid in the presence of amines (Section 2.3, Scheme 8).

Selective N-Monomethylation of Primary Anilines
Primary anilines 92 were selectively monomethylated [43] by reaction with BTM and NaH in DMF (Scheme 29).Tuning the reaction condition and the equivalents of BTM and TFA, as shown in Scheme 27, to go beyond the reduction, obtaining a different product [41].A reduced amount of BTM, increased equivalents of TFA and the use of an aprotic solvent brought to the N-trifluoroacetylated indolines 86, while the increase of BTM brought to the Ntrifluoroethylated indolines 87, similarly to the reduction, by BTM, of carboxylic acid in the presence of amines (Section 2.3, Scheme 8).Tuning the reaction condition and the equivalents of BTM and TFA, as shown in Scheme 27, to go beyond the reduction, obtaining a different product [41].A reduced amount of BTM, increased equivalents of TFA and the use of an aprotic solvent brought to the N-trifluoroacetylated indolines 86, while the increase of BTM brought to the Ntrifluoroethylated indolines 87, similarly to the reduction, by BTM, of carboxylic acid in the presence of amines (Section 2.3, Scheme 8).

Selective N-Monomethylation of Primary Anilines
Primary anilines 92 were selectively monomethylated [43] by reaction with BTM and NaH in DMF (Scheme 29).The synthetic method was successfully extended to the synthesis of N-trifluoroethylated tetrahydroquinoline 89 and N-trifluoroethylated tetrahydroquinoxalines 91 (Scheme 28) [42].Tuning the reaction condition and the equivalents of BTM and TFA, as shown in Scheme 27, to go beyond the reduction, obtaining a different product [41].A reduced amount of BTM, increased equivalents of TFA and the use of an aprotic solvent brought to the N-trifluoroacetylated indolines 86, while the increase of BTM brought to the Ntrifluoroethylated indolines 87, similarly to the reduction, by BTM, of carboxylic acid in the presence of amines (Section 2.3, Scheme 8).

Selective N-Monomethylation of Primary Anilines
Primary anilines 92 were selectively monomethylated [43] by reaction with BTM and NaH in DMF (Scheme 29).Tuning the reaction condition and the equivalents of BTM and TFA, as shown in Scheme 27, to go beyond the reduction, obtaining a different product [41].A reduced amount of BTM, increased equivalents of TFA and the use of an aprotic solvent brought to the N-trifluoroacetylated indolines 86, while the increase of BTM brought to the Ntrifluoroethylated indolines 87, similarly to the reduction, by BTM, of carboxylic acid in the presence of amines (Section 2.3, Scheme 8).

Selective N-Monomethylation of Primary Anilines
Primary anilines 92 were selectively monomethylated [43] by reaction with BTM and NaH in DMF (Scheme 29).In the proposed reaction mechanism (Scheme 30), the first step is the reaction of aniline 92 with NaH and DMF obtaining amidine 94 that, likewise, the reduction of imines by BTM [2], is reduced to aminal 95; subsequent elimination of dimethylamine generated an imine that is easily reduced to the final product.
In the proposed reaction mechanism (Scheme 30), the first step is the reaction of aniline 92 with NaH and DMF obtaining amidine 94 that, likewise, the reduction of imines by BTM [2], is reduced to aminal 95; subsequent elimination of dimethylamine generated an imine that is easily reduced to the final product.The sources of the hydrogens of the methyl group in monomethyl anilines 93 (in red and green in Scheme 30) and the easy synthesis of BTM-D3 (Me3N•BD3) by deuterium exchange in acidic D2O [2] were exploited in the synthesis of products with specific numbers of deuterium atoms into the methyl groups (Scheme 31) and excellent deuterium incorporation ratio, based on which deuterated reagent was used for the reaction.

Reduction of Nitrobenzenes to Anilines
BTM is hydrolytically stable in alcohols, but it can be activated in situ through palladium catalysis [44], and the reaction can be coupled with the reduction of nitroaryls 94 to anilines 95 (Scheme 32).Measuring the kinetic of the reaction pointed out that the reduction was faster than hydrogen liberation: BTM acted as hydrogen-transfer reagent and palladium hydride likely as the transient species; indeed, the reaction was an open vessel reduction, even performed at reflux, without concomitant loss of hydrogen.The sources of the hydrogens of the methyl group in monomethyl anilines 93 (in red and green in Scheme 30) and the easy synthesis of BTM-D 3 (Me 3 N•BD 3 ) by deuterium exchange in acidic D 2 O [2] were exploited in the synthesis of products with specific numbers of deuterium atoms into the methyl groups (Scheme 31) and excellent deuterium incorporation ratio, based on which deuterated reagent was used for the reaction.In the proposed reaction mechanism (Scheme 30), the first step is the reaction of aniline 92 with NaH and DMF obtaining amidine 94 that, likewise, the reduction of imines by BTM [2], is reduced to aminal 95; subsequent elimination of dimethylamine generated an imine that is easily reduced to the final product.The sources of the hydrogens of the methyl group in monomethyl anilines 93 (in red and green in Scheme 30) and the easy synthesis of BTM-D3 (Me3N•BD3) by deuterium exchange in acidic D2O [2] were exploited in the synthesis of products with specific numbers of deuterium atoms into the methyl groups (Scheme 31) and excellent deuterium incorporation ratio, based on which deuterated reagent was used for the reaction.

Reduction of Nitrobenzenes to Anilines
BTM is hydrolytically stable in alcohols, but it can be activated in situ through palladium catalysis [44], and the reaction can be coupled with the reduction of nitroaryls 94 to anilines 95 (Scheme 32).Measuring the kinetic of the reaction pointed out that the reduction was faster than hydrogen liberation: BTM acted as hydrogen-transfer reagent and palladium hydride likely as the transient species; indeed, the reaction was an open vessel reduction, even performed at reflux, without concomitant loss of hydrogen.

Reduction of Nitrobenzenes to Anilines
BTM is hydrolytically stable in alcohols, but it can be activated in situ through palladium catalysis [44], and the reaction can be coupled with the reduction of nitroaryls 94 to anilines 95 (Scheme 32).Measuring the kinetic of the reaction pointed out that the reduction was faster than hydrogen liberation: BTM acted as hydrogen-transfer reagent and palladium hydride likely as the transient species; indeed, the reaction was an open vessel reduction, even performed at reflux, without concomitant loss of hydrogen.
Molecules 2024, 29, 12 of 23 In the proposed reaction mechanism (Scheme 30), the first step is the reaction of aniline 92 with NaH and DMF obtaining amidine 94 that, likewise, the reduction of imines by BTM [2], is reduced to aminal 95; subsequent elimination of dimethylamine generated an imine that is easily reduced to the final product.The sources of the hydrogens of the methyl group in monomethyl anilines 93 (in red and green in Scheme 30) and the easy synthesis of BTM-D3 (Me3N•BD3) by deuterium exchange in acidic D2O [2] were exploited in the synthesis of products with specific numbers of deuterium atoms into the methyl groups (Scheme 31) and excellent deuterium incorporation ratio, based on which deuterated reagent was used for the reaction.

Reduction of Nitrobenzenes to Anilines
BTM is hydrolytically stable in alcohols, but it can be activated in situ through palladium catalysis [44], and the reaction can be coupled with the reduction of nitroaryls 94 to anilines 95 (Scheme 32).Measuring the kinetic of the reaction pointed out that the reduction was faster than hydrogen liberation: BTM acted as hydrogen-transfer reagent and palladium hydride likely as the transient species; indeed, the reaction was an open vessel reduction, even performed at reflux, without concomitant loss of hydrogen.Credits of the reaction were excellent yield and operationally simple work-up procedure as both byproducts 96 and 97 were removed by simple concentration, and BTM surplus was completely consumed by methanolysis.
A practical use of this procedure was the "one pot" multigram synthesis of pyridine 99 (Scheme 33), a key intermediate in the synthesis of quinolone 100, a subtype-selective GABA-A receptor inverse agonist [45].
Molecules 2024, 29, 2017 13 of 23 Credits of the reaction were excellent yield and operationally simple work-up procedure as both byproducts 96 and 97 were removed by simple concentration, and BTM surplus was completely consumed by methanolysis.
A practical use of this procedure was the "one pot" multigram synthesis of pyridine 99 (Scheme 33), a key intermediate in the synthesis of quinolone 100, a subtype-selective GABA-A receptor inverse agonist [45].

Reductive Deprotection of N-Tritylamines
BTM reacts with some carbenium ions [11] by hydride abstraction; this reaction was exploited for the trapping of trityl cation in the deprotection of N-tritylamines, especially for sensitive substrates such as N-tritylaziridine 101 (Scheme 34) [46,47], an intermediate in the synthesis of aziridinomitosenes.In addition, the method was tested for the deprotection of the aziridines 103 and 104 [48] with a low yield in the latter case due to problems with aziridine ring opening; in the absence of potential complications, the yields were excellent as for the protected serine 105 [48] and intermediate 106 in the synthesis of phytosphingosines [49].

Photocatalytic Difluoromethylation of Unactivated Alkenes
Ligated boryl radicals, with the general formula LB + -R2B •− , are intermediates in the activation of halogenated compounds by a reaction of halogen atom transfer (XAT) owing to the nucleophilic character of boryl radicals.Exploiting this process, BTM was utilized for the photocatalytic trifluoromethylation [50] of unactivated alkenes 107 by activation of Freon-22 108, an inexpensive feedstock, under 456 nm blue LED light irradiation (Scheme 35).

Reductive Deprotection of N-Tritylamines
BTM reacts with some carbenium ions [11] by hydride abstraction; this reaction was exploited for the trapping of trityl cation in the deprotection of N-tritylamines, especially for sensitive substrates such as N-tritylaziridine 101 (Scheme 34) [46,47], an intermediate in the synthesis of aziridinomitosenes.
Molecules 2024, 29, 2017 13 of 23 Credits of the reaction were excellent yield and operationally simple work-up procedure as both byproducts 96 and 97 were removed by simple concentration, and BTM surplus was completely consumed by methanolysis.
A practical use of this procedure was the "one pot" multigram synthesis of pyridine 99 (Scheme 33), a key intermediate in the synthesis of quinolone 100, a subtype-selective GABA-A receptor inverse agonist [45].

Reductive Deprotection of N-Tritylamines
BTM reacts with some carbenium ions [11] by hydride abstraction; this reaction was exploited for the trapping of trityl cation in the deprotection of N-tritylamines, especially for sensitive substrates such as N-tritylaziridine 101 (Scheme 34) [46,47], an intermediate in the synthesis of aziridinomitosenes.In addition, the method was tested for the deprotection of the aziridines 103 and 104 [48] with a low yield in the latter case due to problems with aziridine ring opening; in the absence of potential complications, the yields were excellent as for the protected serine 105 [48] and intermediate 106 in the synthesis of phytosphingosines [49].

Photocatalytic Difluoromethylation of Unactivated Alkenes
Ligated boryl radicals, with the general formula LB + -R2B •− , are intermediates in the activation of halogenated compounds by a reaction of halogen atom transfer (XAT) owing to the nucleophilic character of boryl radicals.Exploiting this process, BTM was utilized for the photocatalytic trifluoromethylation [50]  In addition, the method was tested for the deprotection of the aziridines 103 and 104 [48] with a low yield in the latter case due to problems with aziridine ring opening; in the absence of potential complications, the yields were excellent as for the protected serine 105 [48] and intermediate 106 in the synthesis of phytosphingosines [49].

Photocatalytic Difluoromethylation of Unactivated Alkenes
Ligated boryl radicals, with the general formula L B + -R 2 B •− , are intermediates in the activation of halogenated compounds by a reaction of halogen atom transfer (XAT) owing to the nucleophilic character of boryl radicals.Exploiting this process, BTM was utilized for the photocatalytic trifluoromethylation [50] of unactivated alkenes 107 by activation of Freon-22 108, an inexpensive feedstock, under 456 nm blue LED light irradiation (Scheme 35).
Difluoromethylated product 110 is of enormous interest in pharmaceutical and agrochemical science owing to the properties of the group CF 2 H, bioisostere of hydroxyl, thiol, and amine groups.Alkenes suitable for the reaction protocol were extremely broad with the limitation of sterically encumbered tetra-substituted alkenes, unreactive, styrenes and electron-deficient alkenes where the reduction was a competitive reaction.The tolerance of various functional groups was also proved in the late-stage functionalization of complex pharmaceutical molecules and natural products; the yields were generally good, with limited examples with low yields.Supported by experimental and calculation results, the proposed mechanism of the reaction is shown in Scheme 36.Difluoromethylated product 110 is of enormous interest in pharmaceutical and agrochemical science owing to the properties of the group CF2H, bioisostere of hydroxyl, thiol, and amine groups.Alkenes suitable for the reaction protocol were extremely broad with the limitation of sterically encumbered tetra-substituted alkenes, unreactive, styrenes and electron-deficient alkenes where the reduction was a competitive reaction.The tolerance of various functional groups was also proved in the late-stage functionalization of complex pharmaceutical molecules and natural products; the yields were generally good, with limited examples with low yields.Supported by experimental and calculation results, the proposed mechanism of the reaction is shown in Scheme 36.Aryl thiyl radical 116 is generated from disulfide homolysis under blue light irradiation and subsequently reduced to thiolate 116 by the excited state of 109; the produced oxidized form 109 .+ is reduced back by BTM generating the amine-boryl radical 114 that undergoes a XAT reaction with Freon-22 108 to generate the transient radical 111.Subsequently, the intermolecular radical addition with the alkene substrate 107 and the quench of the radical adduct 113 by thiol 117 completed the reaction.

Reductive Cleavage of Acetals
Regioselective cleavage of cyclic acetals in the presence of a Lewis acid is the main application of BTM in the field of organic synthesis, and it is almost completely related to Difluoromethylated product 110 is of enormous interest in pharmaceutical and agrochemical science owing to the properties of the group CF2H, bioisostere of hydroxyl, thiol, and amine groups.Alkenes suitable for the reaction protocol were extremely broad with the limitation of sterically encumbered tetra-substituted alkenes, unreactive, styrenes and electron-deficient alkenes where the reduction was a competitive reaction.The tolerance of various functional groups was also proved in the late-stage functionalization of complex pharmaceutical molecules and natural products; the yields were generally good, with limited examples with low yields.Supported by experimental and calculation results, the proposed mechanism of the reaction is shown in Scheme 36.Aryl thiyl radical 116 is generated from disulfide homolysis under blue light irradiation and subsequently reduced to thiolate 116 by the excited state of 109; the produced oxidized form 109 .+ is reduced back by BTM generating the amine-boryl radical 114 that undergoes a XAT reaction with Freon-22 108 to generate the transient radical 111.Subsequently, the intermolecular radical addition with the alkene substrate 107 and the quench of the radical adduct 113 by thiol 117 completed the reaction.

Reductive Cleavage of Acetals
Regioselective cleavage of cyclic acetals in the presence of a Lewis acid is the main application of BTM in the field of organic synthesis, and it is almost completely related to Scheme 36.Proposed mechanism of the reaction.
Aryl thiyl radical 116 is generated from disulfide homolysis under blue light irradiation and subsequently reduced to thiolate 116 by the excited state of 109; the produced oxidized form 109 .+ is reduced back by BTM generating the amine-boryl radical 114 that undergoes a XAT reaction with Freon-22 108 to generate the transient radical 111.Subsequently, the intermolecular radical addition with the alkene substrate 107 and the quench of the radical adduct 113 by thiol 117 completed the reaction.

Reductive Cleavage of Acetals
Regioselective cleavage of cyclic acetals in the presence of a Lewis acid is the main application of BTM in the field of organic synthesis, and it is almost completely related to carbohydrate chemistry.Carbohydrates protected as 4,6-O-benzylidene acetals were regioselectively reduced by BTM in the presence of AlCl 3 , forming a free alcohol at one position and a benzyl ether protection at the other, useful for further modifications; Scheme 37 shows an example [93].
Molecules 2024, 29, 2017 15 carbohydrate chemistry.Carbohydrates protected as 4,6-O-benzylidene acetals were oselectively reduced by BTM in the presence of AlCl3 , forming a free alcoh one position and a benzyl ether protection at the other, useful for further modificat Scheme 37 shows an example [93].
Acetals 122 (Scheme 39) with R different from the phenyl group allowed us t the reduced product 123 with a hydroxyl protected with a different protecting g stead of the benzyl group, allowing more flexibility in the synthesis.Several ex were reported in the literature for R = pMeOPh (for six [135][136][137][138] and five [139] me cyclic acetals), 2-naphthyl (for six- [140][141][142][143][144][145] and five-[146-148] membered cyclic and vinyl (five-membered cyclic acetals [149]).The reaction was extensively investigated, and an early study [150] showed addition of two equivalents of water to the reaction mixture (four equivalents of B six equivalents of AlCl3) improved the efficiency of benzylidene reductive cleava out the observation of products of benzylidene acetal hydrolysis and rate enhance approximately four times.In order to decipher the mechanistic details of the react eral model compounds, kinetic experiments, 11 B NMR spectroscopy, computation lations, deuterium labeling, alternative reducing reagents and solvents were use 154], bringing to the proposed mechanism for the reaction in THF, where the Le is complexed to the solvent (Scheme 40).In the first step, BTM is activated by AlC ing the borane the most electrophilic species and leading to the interaction with t electron-rich oxygen in intermediate 126, whilst the driving force is the formatio highly stabilized AlCl3•NMe3 125; the opening of the acetal is obtained by the act second Lewis acid molecule with the formation of an oxocarbenium ion 127 as t Acetals 122 (Scheme 39) with R different from the phenyl group allowed us to obtain the reduced product 123 with a hydroxyl protected with a different protecting group instead of the benzyl group, allowing more flexibility in the synthesis.Several examples were reported in the literature for R = pMeOPh (for six [135][136][137][138] and five [139] membered cyclic acetals), 2-naphthyl (for six- [140][141][142][143][144][145] and five- [146][147][148] membered cyclic acetals) and vinyl (five-membered cyclic acetals [149]).
Acetals 122 (Scheme 39) with R different from the phenyl group allowed u the reduced product 123 with a hydroxyl protected with a different protectin stead of the benzyl group, allowing more flexibility in the synthesis.Severa were reported in the literature for R = pMeOPh (for six [135][136][137][138] and five [139] cyclic acetals), 2-naphthyl (for six- [140][141][142][143][144][145] and five- [146][147][148] membered cy and vinyl (five-membered cyclic acetals [149]).The reaction was extensively investigated, and an early study [150] show addition of two equivalents of water to the reaction mixture (four equivalents o six equivalents of AlCl3) improved the efficiency of benzylidene reductive clea out the observation of products of benzylidene acetal hydrolysis and rate enha approximately four times.In order to decipher the mechanistic details of the re eral model compounds, kinetic experiments, 11 B NMR spectroscopy, computat lations, deuterium labeling, alternative reducing reagents and solvents were 154], bringing to the proposed mechanism for the reaction in THF, where the is complexed to the solvent (Scheme 40).In the first step, BTM is activated by A ing the borane the most electrophilic species and leading to the interaction wi electron-rich oxygen in intermediate 126, whilst the driving force is the forma highly stabilized AlCl3•NMe3 125; the opening of the acetal is obtained by the second Lewis acid molecule with the formation of an oxocarbenium ion 127 Scheme 39.Cleavage of cyclic acetals 122.
The reaction was extensively investigated, and an early study [150] showed that the addition of two equivalents of water to the reaction mixture (four equivalents of BTM and six equivalents of AlCl 3 ) improved the efficiency of benzylidene reductive cleavage without the observation of products of benzylidene acetal hydrolysis and rate enhancement of approximately four times.In order to decipher the mechanistic details of the reaction, several model compounds, kinetic experiments, 11 B NMR spectroscopy, computational calculations, deuterium labeling, alternative reducing reagents and solvents were used [151][152][153][154], bringing to the proposed mechanism for the reaction in THF, where the Lewis acid is complexed to the solvent (Scheme 40).In the first step, BTM is activated by AlCl 3 , making the borane the most electrophilic species and leading to the interaction with the most electron-rich oxygen in intermediate 126, whilst the driving force is the formation of the highly stabilized AlCl 3 •NMe 3 125; the opening of the acetal is obtained by the action of a second Lewis acid molecule with the formation of an oxocarbenium ion 127 as the rate-controlling step; finally, oxocarbenium ion is then reduced with low stereoselectivity to give product 128.
The reaction in toluene had different regioselectivity and usually gave low yields due to degradation.In this case, in the proposed mechanism (Scheme 41), the strongest Lewis acid is AlCl 3, which reacts very fast to give the oxocarbenium ion 130 that is then reduced by BTM, with low stereoselectivity to give product 131.
controlling step; finally, oxocarbenium ion is then reduced with low stereoselectivity to give product 128.Scheme 40.Proposed mechanism for the reaction in THF.
The reaction in toluene had different regioselectivity and usually gave low yields due to degradation.In this case, in the proposed mechanism (Scheme 41), the strongest Lewis acid is AlCl3, which reacts very fast to give the oxocarbenium ion 130 that is then reduced by BTM, with low stereoselectivity to give product 131.Scheme 41.Proposed mechanism for the reaction in toluene.

Conclusions
In conclusion, BTM has several credits as a reagent in modern organic synthesis.It is relatively inexpensive, and considering its low molecular weight, it has a low price per mole.It is a stable solid with a good safety profile linked with its relative inertness.Its reactivity can be opportunely activated in the reaction medium, generally in the presence of Lewis or Brønsted acids.BTM undergoes rapid deuterium exchange in acidic D2O, allowing easy conversion to BTM-D3, an effective reagent for the synthesis of deuteriumlabeled compounds.BTM is very soluble in a wide variety of solvents, offering more ver- The reaction in toluene had different regioselectivity and usually gave low yields due to degradation.In this case, in the proposed mechanism (Scheme 41), the strongest Lewis acid is AlCl3, which reacts very fast to give the oxocarbenium ion 130 that is then reduced by BTM, with low stereoselectivity to give product 131.Scheme 41.Proposed mechanism for the reaction in toluene.

Conclusions
In conclusion, BTM has several credits as a reagent in modern organic synthesis.It is relatively inexpensive, and considering its low molecular weight, it has a low price per mole.It is a stable solid with a good safety profile linked with its relative inertness.Its reactivity can be opportunely activated in the reaction medium, generally in the presence of Lewis or Brønsted acids.BTM undergoes rapid deuterium exchange in acidic D2O, allowing easy conversion to BTM-D3, an effective reagent for the synthesis of deuteriumlabeled compounds.BTM is very soluble in a wide variety of solvents, offering more ver-Scheme 41.Proposed mechanism for the reaction in toluene.

Conclusions
In conclusion, BTM has several credits as a reagent in modern organic synthesis.It is relatively inexpensive, and considering its low molecular weight, it has a low price per mole.It is a stable solid with a good safety profile linked with its relative inertness.Its reactivity can be opportunely activated in the reaction medium, generally in the presence of Lewis or Brønsted acids.BTM undergoes rapid deuterium exchange in acidic D 2 O, allowing easy conversion to BTM-D 3 , an effective reagent for the synthesis of deuterium-labeled compounds.BTM is very soluble in a wide variety of solvents, offering more versatility in the reaction options.The tolerance of various functional groups was a well-substantiated feature of this reagent.The main application of BTM is the regioselective cleavage of cyclic acetals, a reaction of great importance for carbohydrate chemistry.Carbon-nitrogen double bond reduction is another class of reactions where the activation by acids plays an important role in the BTM reactivity.Finally, recent findings in organocatalysis have contributed to develop some innovative applications of BTM, such as the CO 2 utilization as feedstock and the radical chemistry by photocatalysis.
Funding: This research received no external funding.

Scheme 1 .
Scheme 1.Regioselective reduction of dione 1 on a silica gel surface.

Scheme 7 .
Scheme 7. Reaction mechanism of the acid reduction.

Scheme 7 .
Scheme 7. Reaction mechanism of the acid reduction.

Scheme 7 .
Scheme 7. Reaction mechanism of the acid reduction.

Scheme 7 .
Scheme 7. Reaction mechanism of the acid reduction.

Scheme 10 .Scheme 11 .
Scheme 10.The proposed mechanism of the reaction of monomethylation.

Scheme 10 .Scheme 9 .
Scheme 10.The proposed mechanism of the reaction of monomethylation.Recently, the selective methylation of amines with CO2 was examined[23] by combining the organocatalyst 6-amino-2-picoline 36 and BTM (Scheme 11) to form a stable intramolecular frustrated Lewis pairs catalyst (Scheme 12), most of the secondary amines 35 used were N-alkyl or N-aryl anilines, with only two examples of alkyl heterocyclic amines, affording methylation products 37 in moderate to good yields.

Scheme 10 .
Scheme 10.The proposed mechanism of the reaction of monomethylation.

Scheme 12 .
Scheme 12. Reaction mechanism of methylation of amines with CO 2 .On the basis of a series of control experiments, NMR and high-resolution mass spectrometry (HRMS) analyses, a possible reaction mechanism was proposed (Scheme 12).The first step is the reaction of 6-amino-2-picoline 36 and excess BTM leading to aminoborane 38, with the quantitative evolution of H 2 , followed by the CO 2 activation with zwitterionic intermediate 39.The next steps are less evident, and the authors speculate the formation of intermediate 40 that is further reduced to product 37.Without a catalyst, halving the equivalents of BTM and with DMF as solvent (Scheme 13), the reduction afforded the corresponding monoformylation products 41, an intermediate hypothesized in the reduction from 40 to product 37 (Scheme 12); most of the amines 35 used were primary anilines and yields were generally good.
Scheme 12. Reaction mechanism of methylation of amines with CO2.

Scheme 17 .
Scheme 17.The proposed mechanism of the synthesis of hydrazides.

Scheme 17 .
Scheme 17.The proposed mechanism of the synthesis of hydrazides.

Scheme 16 . 23 Scheme 15 .
Scheme 16.Reduction of hydrazones and azines.The work-up operationally simple was another credit of the method, as the byproduct of reduction 56 (Scheme 17) was soluble in toluene, contrary to products 51 or 53, which are completely insoluble (except for two compounds) and easily separated by filtration.

Scheme 17 .
Scheme 17.The proposed mechanism of the synthesis of hydrazides.

Scheme 30 .
Scheme 30.Proposed reaction mechanism of the monomethylation of anilines.

Scheme 30 .
Scheme 30.Proposed reaction mechanism of the monomethylation of anilines.

Scheme 30 .
Scheme 30.Proposed reaction mechanism of the monomethylation of anilines.

Scheme 36 .
Scheme 36.Proposed mechanism of the reaction.

Scheme 36 .
Scheme 36.Proposed mechanism of the reaction.